Open Development and Clinical Validation Of Multiple 3D-Printed Sample-Collection Swabs: Rapid Resolution of a Critical COVID-19 Testing Bottleneck

Abstract

The SARS-CoV-2 pandemic has caused a severe international shortage of the nasopharyngeal swabs that are required for collection of optimal specimens, creating a critical bottleneck in the way of high-sensitivity virological testing for COVID-19. To address this crisis, we designed and executed an innovative, radically cooperative, rapid-response translational-research program that brought together healthcare workers, manufacturers, and scientists to emergently develop and clinically validate new swabs for immediate mass production by 3D printing. We performed a rigorous multi-step preclinical evaluation on 160 swab designs and 48 materials from 24 companies, laboratories, and individuals, and shared results and other feedback via a public data repository (http://github.com/rarnaout/Covidswab/). We validated four prototypes through an institutional review board (IRB)-approved clinical trial that involved 276 outpatient volunteers who presented to our hospital's drive-through testing center with symptoms suspicious for COVID-19. Each participant was swabbed with a reference swab (the control) and a prototype, and SARS-CoV-2 reverse-transcriptase polymerase chain reaction (RT-PCR) results were compared. All prototypes displayed excellent concordance with the control (κ=0.85-0.89). Cycle-threshold (Ct) values were not significantly different between each prototype and the control, supporting the new swabs' non-inferiority (Mann-Whitney U [MWU] p>0.05). Study staff preferred one of the prototypes over the others and the control swab overall. The total time elapsed between identification of the problem and validation of the first prototype was 22 days. Contact information for ordering can be found at http://printedswabs.org. Our experience holds lessons for the rapid development, validation, and deployment of new technology for this pandemic and beyond.

Figure 1:

Control and prototype swabs. (a) From left to right: the control swab (Copan 501CS01), a repurposed urogenital cleaning swab approved for NP testing through our process, Prototype 1 (Resolution Medical), Prototype 2 (EnvisionTec), Prototype 3 (Origin.io), and Prototype 4 (Hewlett Packard). (b) From top to bottom, closeups of the heads of the swabs in (a). Scale bars, 1cm. (c) Examples of Gram stain of cheek swab using control (top) and prototype swabs. Scale bar, 10μm. (d) Examples of materials testing. Clockwise from top left: head flexibility and robustness to fracture, neck flexibility and robustness to fracture, robustness to repeat insertion into and removal from a tortuous canal (diameter 3cm), and breakpoint evaluation.

Figure 2:. Concordance results.

(a) 2×2 tables giving counts for each prototype vs. the control swab (first three panels) and for control vs. replicate control obtained within 24 hours on the same individual. Discordant results in gray; totals for each swab below and to the right of each box; total number of pairs in bold; K=Cohen’s kappa. (b) Scatterplot of Ct values for pairs of swabs for which at least one swab was SARS-CoV-2 positive. For discordant pairs, the negative swab was assigned a Ct value of 37 (the maximum number of cycles run).

Figure 3:. Subjective feedback.

(a) Round-robin A-B testing of net preferences among Prototypes 1–3 (large bold numbers) and the control (“C”). Each arrow points from the less preferred to the more preferred swab. Arrow weight indicates strength of relative preference. Preferences were unanimous except where noted with numbers separated by a slash: the first number denotes the number of responses for the direction indicated by the arrowhead, while the second number denotes the number of responses that had the opposite preference. The weight of the arrow is proportional to the difference (e.g. 7–3=a net preference of 4). Unless noted, each arrow denotes 12–15 separate responses. (b) Number of positive and negative comments received from study staff who administered the swabs, tabulated by category. In each plot, negative feedback is to the left of the zero, while positive feedback is to the right. Bars on both the positive and negative sides of zero reflect differing opinions among study staff. n, total number of comments received about each prototype.